Signal transducers and activators of transcription (STAT) proteins function as both cytokines and transcription factors. Upregulation of STAT3 is found in many human cancers, including breast, prostate, and melanoma. This continuous activation has been found to enhance tumor cell survival, proliferation, angiogenesis, and metastasis, while also simultaneously reducing immune surveillance. Given the role of aberrant STAT3 activity in promoting cancer, targeting aberrant STAT3 activity is an attractive target for anti-cancer therapy. We have found that in melanoma, STAT3 is also upregulated in response to BRAF and MEK inhibition. Furthermore, targeting the STAT3 pathway in combination with MEK inhibitors prevents the invasive phenotype of melanoma cell lines. Despite the indication that STAT3 is a viable target, there are no clinically effective inhibitors currently in use. The S2 domain of STAT3 contains a druggable pocket that recognizes phosphor- Tyr and is essential for STAT3 activity. We previously developed quinolol/naphthol compounds that inhibit STAT3 activity, which we hypothesize function by binding to the SH2 phospho-binding domain. While other SH2 inhibitors exist, there is currently no structural data available of inhibitors bound to he STAT3 SH2 domain. We propose a combination of biochemical and structural techniques to characterize the binding mode of these STAT3 inhibitors. The combined studies will characterize protein binding of a novel family of STAT3 inhibitors and develop them for potency and selectivity in vitro and activity in cancer cells. The inhibitors may also form lead compounds for future drug development for the treatment of melanoma and other cancer types.